Immunogens inducing protective, disease-sparing CD8+ T cell responses are a primary focus of research efforts at the VRC. DNA vaccines are the chief platform of vaccine candidates currently. While DNA immunogens can generate CD8+ CTL responses, administration of large quantities of DNA is required to induce immunity. These studies are designed to identify interventions that will increase the efficiency of DNA immunization and to optimize the conditions of each intervention. Interventions that will be investigated include the use of ultrasound at the injection site, co-administration of MVA or vaccinia virus, and DNA complexed to nanoparticles. With the identification of procedures that increase the uptake and/or expression of vaccine DNA, the administration of less DNA would be required, making the use of DNA vaccines more widely applicable, particularly in developing countries. Additionally, vector-based immunogens expressing matched codon-modified viral proteins will be evaluated for their relative abilities to induce virus-specific immune responses. Specifically, the magnitude and the quality of the immune responses induced by each vector will be compared using murine prime-challenge models.